6-substittuted ionones and methods and intermediates used in their production



United States Patent ce The present invention relates to compositionsand processes for the synthesis of irones and other 6-substitutedionones.

a-Irone, which possesses the general formula is a principal component ofthe perfume of violets and finds considerable use in the perfumeindustry. The synthetic routes leading to irone which have thus far beenreported comprise a large number of steps and there is, therefore, ademand for a simpler route comprising comparatively few steps.

In accordance with this invention, irone and related compounds areproduced from the available compound IP-iOI'lOHe by a simplifiedprocedure using as an essential intermediate a novel epoxide of ldOllOiW. When &- ionone, which has the formula is reacted with reagentswhich convert a carbon-carbon double bond to an epoxide group, moreparticularly organic per acids, for example perbenzoic acid,monoperphthalic acid and peracetic acid, the unconjugated double bondcan be selectively epoxidised and the compound having the formula isformed in good yield. The reaction may be carried out by reacting,b-ionone preferably in solution in an inert solvent, for example etheror benzene, with an organic per acid, such as peracetic acid, perbenzoicaicd or monoperphthalic acid. The reaction is advantageously carried outat reduced temperatures, for example 0 C.

The epoxide H, which is a new compound, is a particularly usefulintermediate in the synthesis of known synthetic perfumes and ofhitherto unprepared perfume analogues. By reaction of II, after suitableprotection of the ketonic carbonyl, with Grignard reagents, or metalalkyls, it is possible to form ketols which may be cyclised to 6-alkylionones. Thus, by using a methylating metal derivative it is possible toprepare the 6-methyl-ionone,

rrone.

'or aralltyl groups.

3,ll7,982 Patented Jan. 14-, 1964 The particular utility of epoxide IIin perfume synthesis is illustrated by the following synthesis of irone.

In step (a) the keto group of epoxide II is protected by reduction to ahydroxyl group to avoid reaction with the Grignard reagent used in thenext step. The reduction, which should be achieved without substantialreduction of the epoxide or of the conjugated double bonds, isconveniently carried out using a metal hydride reducing agent such assodium borohydride. It is, however, possible to protect the keto groupby means other than reduction. Thus, for example, the ketoxiine may beformed by reaction with hydroxylamine or the semicarbazone withsemicarbazide. In general, the protecting group should not react withthe Grignard or other alkyiating reagent used in the next step or shouldreact more slowly than does the epoxide. Formation of the ketalderivative does not however, appear to be a satisfactory means ofprotection.

in step (b) or" the reaction sequence, the epoxyalcohol iii is reactedwith an organometallic compound. Where fi-substituted ionones other thanirone are required, the organometallic compound may carry other alkylgroups As an alternative to magnesium derivatives, it is possible to usealkali metal alkyls such as lithium alkyls. The reaction is preferablycarried out in an inert solvent under anhydrous conditions using anexcess of the organometallic compound.

The oxidation step (0) shown in the above reaction route may beaccomplished in any convenient way, advantageously using activemanganese dioxide. Where, however, the keto group was protected, not byreduction but by conversion to a protected grouping, other methods arerequired to reform the keto group. Thus, for example, where an oxime ora semicarbazide is formed as the protected group, mild hydrolysis withdilute mineral acid yields the desired keto group.

The cyclisation step (d) shown in the above reaction route may beconveniently carried out by contacting the ketol V with a cyclisingagent. Suitable cyclising agents include strong mineral acids, such assulphuric acid, phosphoric acid or toluene sulphonic acid, and Lewisacids, such as boron trifluoride.

lonones exist in three principal isomeric forms which ditIer in thepositioning of the double bond adjoining the 3-position as shown below.

O H II B-Ionone 'y-lonone 110110116 The order of stability of theseforms appears to be ,8 or 'y and it is found that in the presence of astrong acid or a Lewis acid and under rigorous conditions, y-ionone isconverted to a-ionone which, if the conditions are sufficientlyrigourous, is converted to fl-ionone. The rigour of the conditions isdetermined principally by the temperature and the presence or absence ofa polar solvent, as well as by the nature of the strong acid or Lewisacid used.

In order to obtain a-irone, for example the ketol V may be cyclised byaddition into concentrated aqueous phosphoric acid. Addition of theketol V to a solution of boron trifluoride in a non-polar solvent, forexample ether, leads, however, to -irone while addition to a boilingaqueous solution of sulphuric or phosphoric acid yields the fi-isomer.

Similar results are obtained on direct cyclisation of the epoxide II,forcing conditions yielding 6-hydroxy-fiionone, while milder conditionslead to the aor 'yisomers. The 6-hydroxy derivatives so formed may beoxidised to 6-keto derivatives, for example with chromium trioxide and,if the sidechain keto group has been protected before oxidation, the6-keto group may be further reacted with, for example, Grignard reagentsto give 6- alkyl-6-hydroxy-ionones.

It will be thus seen that the novel epoxide of rp-ionone according tothe present invention may be simply converted both to the known perfumeot-irone and to other 6-substituted ionones of interest in the perfumeindustry.

In order that the invention may be well understood, we give thefollowing examples by way of illustration only. Melting points are givenin the centigrade scale and were taken on the Kofiler block. Allultra-violet absorption spectra were determined in ethanol using theUnicam SP. 500 spectrophotometer. Infra-red spectra are for the purecompound unless specified to the contrary. Light petroleum refers to thefraction of B.P. 40-60" C.

EXAMPLE 1 b-Ionone Epoxz'de (H) l -lonone g.) in ether (50 ml.) wastreated at 0 with stirring with monoperphthalic acid (15 g.) in the samesolvent (300 ml.) and left for 24 hours. The solution was washedsuccessively with aqueous sodium hydrogen carbonate, with l N aqueoussodium hydroxide and then with water. The dried sodium sulfate solutiongave on distillation zp-ionone epoxide (13 g), 13?. 1l8/0.7 mm., 1.185,A max. 291 me (e=21,000). This was characterised as the2,4-dinitrophenylhydrazone of ,b-ionone epoxide. Prepared by the methodof Brande and Timmons (1., 1953, 3136), this had M.P. (from ethanol)159- 160, A max. 392 me (e=33,000). (Found: C, 58.5; H, 6.05; N, 14.55.C H O N requires C, 58.75; H, 6.25; N, 14.45%.)

EXAMPLE 2 b-Ionol Epoxiae (III) l/-Ionone epoxide (13 g.) in methanol(200 ml.) at 0 was treated with sodium borohydride /2 mol.) until theketom'c function had been reduced [ultra-violet control: disappearanceof the band at 291 m and appearance of a new band (e=2( ,000 approx.) at240 me]. The excess of sodium borohydride was destroyed with acetic acidand then a slight excess of sodium hydrogen carbonate was added. Themethanol was removed in vacuo, the residue extracted into ether, driedsodium sulfate and then distilled to furnish \p-ionol epoxide (12 g.),B.P. /0.2 mm., )t max. 240 m (s=23,000). (Found: C, 73.85; H, 10.55. C HO requires C, 74.25; H, 10.55%.)

EXAMPLE 3 2,3,6-TrimelhyIundeca-6,8-Dien-ZJ 0-D iol Magnesium (6 g.) wasconverted to the Grignard reagent using methyl bromide (20 ml.) inpurified tetrahydrofuranc (200 ml.). To this solution was added slowlywith stirring ,b-ionol epoxide (12 g.) in the same solvent ml.) and leftfor one hour. The reaction mixture was then refluxed for 4 hours,cooled, treated with excess of saturated aqueous ammonium chloride at 0.After ether extraction and drying over sodium sulfate the ether andtetrahydrofurane were removed in vacuo at 40. The residue could not bedistilled due to decomposition but it analysed correctly for theexpected glycol, the 2,3,6-trimethylundeca-6,8-dien-2,10 diol, (IV);max. 240 m (c=25,000). (Found: C, 74.3; H, 11.3. C H O requires C, 74.3;H, 11.6%.)

EXAMPLE 4 2,3,6-TrinzethyIlmdeca-6,8-D[cn-2-Ol-10-One The glycol ofExample 3 (10.3 g.) in dry ether (500 ml.) was shaken with active MnO(105 g.) at room temperature and the progress of the oxidation followedin the ultra-violet. After 48 hours there was no further increase in theintensity of the band at 291 m (e=18,000). Removal of the MnO byfiltration and of the ether in the usual way gave a residue (10 g.)which had 7t max. 291 m (e=l8,000) and showed an OH band in theinfra-red (3625 cmf It was characterised as the ketol (V) by thepreparation of the 2,4-dinitrophenylhydrazone, M.P. (from benzene-lightpetroleum) 173, A max. 392 m (e=32,000). (Found: C, 58.9; H, 7.15;N,14.1.

requires C, 59.4; H, 7.0; N, 13.85%.)

EXAMPLE 5 Synthesis of a-lrone The ketol,2,3,3-trimethylundeca-6,8-dien-2-ol-10-one (10 g.) Was added dropwisewith good stirring to phosphoric acid (90%; 30 ml.) at 30 and themixture stirred for 15 minutes. Excess of ice water was added and thecyciised product extracted into ether. The ether was removed and theresidue steam distilled to give an oil, B.P. 73 /0.3 mm., 11 1.5000, Amax. 228 mu (e=1l,200) and ca. 290 mg (6=2,000), the latter bandindicating the presence of some p-irone. The oil gave a phenylsemicarbazone MP. (initially) raised to 172 on recrystallisation fromethanol. (Found: C, 74.55; H, 8.6; N, 12.5, 12.65. Calc. for C H ON C,74.3; H, 8.6; N, 12.4%.) Authentic synthetic oz-irone gave a derivativeof the same melting point undepressed on admixture. The infra-redspectra (in chloroform) were identical. Conversion to the2,4-dinitrophenylhydrazone and crystallisation from methanol gave aderivative M.P. 103-104", undepressed on admixture with an authenticspecimen of the same melting point prepared from authentic syntheticet-irone through the phenyl semicarbazone of M.P. 172.

Other 6-substituted cyclic ionones are produced in the same manner asthe a-irone described in Examples 1 through 5. For this purpose, thestarting material is /-ionol which may be prepared by following theprocedures of Examples 1 and 2. Example 3 is then followed for thepreparation of the required glycol except that instead of using methylbromide, there is employed an alkyl halide or an aralkyl halide, such asbromide or chloride, containing the alkyl or aralkyl group which isdesired in the 6 position of the substituted cyclic ionone. Forinstance, if a 6-n-propylx-ionone is desired, 6-n-propyl bromide may beused instead of methyl bromide in the procedure of Example 3 to produce2,3-dirnethy1-6-npropyl-6,8-dien-2,lO-diol. This latter glycolconstitutes the starting material for producing the corresponding ketolby following the procedure outlined in Example 4 and the resulting ketolis cyclised as described in Example 5. Again, the 6-benzyl-a-ionone isproduced in the same manner by utilizing a benzyl halide, such as benzylchloride, instead of the methyl bromide in Example 3, and following theprocedures of Examples 4 and with the resulting benzyl reactionproducts.

What is claimed is:

1. 2,6 dirnethyl-3substituted-undeca-6,8-dien-2-ol-10- one having theformula:

in which R is a monovalent group having less than 8 carbon atomsselected from the class consisting of unsubstituted alkyl andunsubstituted aralkyl groups.

2. 2,6 dimethyl-3-unsubstituted alkylundeca-6,8-dien- 2-ol-10-one inwhich the alkyl group has less than 8 carbon atoms.

3. 2,6-dimetnyl-3-unsubstituted aralkylundeca-6,8-dien- 2-ol-10 -one inwhich the aralkyl group has less than 8 carbon atoms.

4. 2,6 dimetliyl 3-substituted-undeca-6,8-dien-2,10- diol having theformula:

in which R is a monovalent group having less than 8 carbon atomsselected from a class consisting of unsubstituted alkyl andunsubstituted ara-lkyl groups.

5. 2,6 dimethyl-3-unsubstituted-alkylundeca-6,8-dien- 2,1-dio1 in whichthe alkyl group has less than 8 carbon atoms.

6. 2,6 dimethyl 3 unsubstituted-aralkylundeca-G,8- dien2,10-dio1 inwhich the aralkyl group has less than 8 carbon atoms.

7. 2,3,6-trimethylundeca-6,8-dien-2,IO-diol.

8. 2,6-dimet'nyl-2,3-epoxyundeca-6,8-diene-10-one.

9. 2,6-dimethyl-2,3-epoxyundeca-6,8-diene-10-01.

10. The ketoxirne of 2,6-dimethyl-2,3-epoxyundeca- 6,8-diene-10-one.

11. The semiearbazone of 2,6-dimethyl-2,3-epoxyundeca-6,8-diene-10-one.

12. The 2,4-dinitrophenylhydrazone of 2,6-dimethyl-2,3-epoxyundeca-6,S-diene-lO-one.

13. In the method of producing a 6-substituted cyclic ionone the step ofreacting b-ionone in solution in an inert solvent with a percarboxylicacid to produce 2,6-dimethyl- 2,3-epoxyundeca-6,8-diene-lO-one, treating2,6-dimethyl- 2,3-ep0xyunde.ca-6,8-diene-l0-one with an alkali metalborohydride until the ketonic group thereof has been reduced to thehydroxyl group, reacting under anhydrous conditions the resulting2,6-dimethyl-2,3-epoxyundeca-6, S-diene-ltl-ol with a Grignard reagenthaving the formula: RMgX, in which X is a halogen selected from theclass consisting of chlorine and bromine and R is a member having lessthan 8 carbon atoms selected from the class consisting of unsubstitutedalkyl groups and unsubstituted aralkyl groups, oxidizing the resulting3-substituted-Z,6-dimethylundeca-6,8-diene-2,ltl-diol with manganesedioxide to produce a3-substituted-2,6-dimethylundeca-6,8-diene-2-ol-10-one and adding slowlythe last mentioned compound to an acid to produce the 6-substitutedcyclic ionone, said acid being selected from the class consisting ofsulphuric acid, phosphoric acid, Lewis acids and toluene sul honic acid.

14. In the method of producing ot-irone, the step of reacting \//iononein solution in an inert solvent with a percarboxylic acid to produce2,6-dimethyl-2,3-epoxyundeca-6,8-diene-10-one, treating2,6-dimethyl-2,3-epoxyundeca-6,8-diene-10-one with an alkali metalborohydride until the ketonic group has been reduced to the hydroxylgroup, reacting under anhydrous conditions the resulting2,6-dimethyl-2,3-epoxyundeca-6,8-diene-10-o1 with a methyl halideGrignard reagent selected from the class consisting of methyl chlorideGrignard reagent and methyl bromide Grignard reagent to produce2,3,6-trimethylundeca- 6,8-diene-2,10-diol, oxidizing the2,3,6-trimethylundeca 6,8-diene-2,10-diol with manganese dioxide toproduce 2,3, 6-trimethylundeca-6,8-diene-2-ol-ltl-one and adding slowlythe last mentioned compound to an acid to produce a-irone, said acidbeing selected from the class consisting of sulphuric acid, phosphoricacid, Lewis acids and toluene sulphonic acid.

References Cited in the file of this patent UNITED STATES PATENTS Kaiseret a1 Mar. 10, 1959 Payne et a1 June 26, 1962 OTHER REFERENCES UNITEDSTATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, 3 ll7 982Januar v 1964 Derek Ho R. Barton It is hereby certified that errorappears in the above numbered patent requiring correction and that thesaid Letters Patent should read as corrected below.

Column 1 line 54L for "aicd" read acid column 3 line 59 for "10185" readM 15185 o Signed and sealed this 9th day of June 19640 (SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No3 117 982 January 14 1964 Derek Ho R Barton It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 1 line 54, for "aicd" read acid column S line 59 for "19185" readl,,5185 =0 Signed and sealed this 9th day of June 1964,

(SEAL) Attest:

EDWARD J. BRENNER Commissioner of Patents ERNEST W; SWIDER firitestingOfficer

1. 2,6-DIMETHYL-3-SUBSTITUTED-UNDECA-6,8-DIEN-2-OL-10ONE HAVING THEFORMULA:
 13. IN THE METHOD OF PRODUCING A 6-SUTSTITUTED CYCLIC IONONETHE STEP OF REACTING $-IONONE IN SOLUTION IN AN INERT SOLVENT WITH APERCARBOXYLIC ACID TO PRODUCE2,3-DIMETHYL2,3-EPOXYUNDECA-6,8-DIENE-10-ONE, TREATING2,3-DIMETHYL2,3-EPOXYUNDECA-6,8-DIENE-10-ONE WITH AN ALKALI METALBOROHYDRIDE UNTIL THE KETONIC GROUP THEREOF HAS BEEN REDUCED TO THEHYDROXYL GROUP, REACTING UNDER ANHYDROUS CONDITIONS THE RESULTING2,6-DIMETHYL-2,3-EPOXYUNDECA-6, 8-DIENE-10-OL WITH A GRIGNARD REAGENTHAVING THE FORMULA: R-MG-X, IN WHICH X IS A HALOGEN SELECTED FROM THECLASS CONSISTING OF CHLORINE AND BROMINE AND R IS A MEMBER HAVING LESSTHAN 8 CARBON ATOMS SELECTED FROM THE CLASS CONSISTING OF UNSUBSTITUTEDALKYL GROUPS AND UNSUBSTITUTED ARALYKL GROUPS, OXIDIZING THE RESULTING3-SUBSTITUTED-2,6-DIMETHYLUNDECA-6,8-DIENE-2,10-DIOL WITH MANGANESEDIOXIDE TO PRODUCE A3-SUBSTITUTED-2,6-DIMETHYLUNDECA-6,8-DIENE-2-OL-10-ONE AND ADDING SLOWLYTHE LAST MENTIONED COMPOUND TO AN ACID TO PRODUCE THE 6-SUBSTITUTEDCYCLIC IONONE, SAID ACID BEING SELECTED FROM THE CLASS CONSISTING OFSULPHURIC ACID, PHOSPHORIC ACID, LEWIS ACIDS AND TOLUENE SULPHONIC ACID.